In the hopes of recreating the successes achieved in other solid malignancies, researchers have evaluated many types of targeted therapy for the treatment of advanced gastric cancer. Regulatory approval of trastuzumab (Herceptin) in 2010 was a step forward, but only a minority of patients is eligible for the human epidermal growth factor receptor 2 (HER2)-targeting antibody therapy.
Success with other targeted agents has been lukewarm, particularly those directed against the epidermal growth factor receptor (EGFR), which has shown no benefit in clinical trials to date and, more recently, MET inhibitors, which also have missed their mark after a promising start.
More recently, studies evaluating ramucirumab (Cyramza), an antiangiogenic therapy that targets the vascular endothelial growth factor receptor 2 (VEGFR2), have translated into a survival benefit in the second-line setting and resulted in regulatory approval last year. Other targeting strategies are also beginning to make headway, and the first reports of immune checkpoint inhibition in gastric cancer emerged in 2014.
Valuable insights have been gathered from both failures and successes; improved molecular characterization of gastric cancer and biomarker identification have emerged as pressing needs. As we enter an era of unprecedented clinical trial activity in gastric cancer, with thousands of patients enrolled or set to be enrolled in large, randomized phase III trials of novel targeted agents, we may finally be on the path to changing the course of this disease (Table)
.Gastric Cancer: an Insidious Foe
Gastric cancer is a major health problem around the world; it is among the five most common types of cancer, with nearly 1 million new diagnoses annually, and was the third-leading cause of cancer-related mortality in 2012, with more than 700,000 deaths annually, according to the World Health Organization.
Surgical resection is the only cure for gastric cancer and, combined with recent improvements in postoperative adjuvant chemotherapy, there have been significant gains in survival for patients with early-stage disease. However, gastric cancer is an insidious disease, often asymptomatic in the early stages, meaning that a vast majority of patients present when the cancer is more advanced and inoperable.
For patients with unresectable, locally recurrent, or metastatic disease, chemotherapy is standard of care (SOC) and a wide variety of combinatorial chemotherapeutic regimens have been developed, but a common feature is their poor efficacy in advanced disease. Thus, these patients have a poor prognosis, with a median survival ranging from 10 to 14 months in advanced diseased.
Advanced gastric cancer represents an enormous unmet medical need and substantial resources have been committed to trying to reproduce the success of targeted therapies in other advanced solid malignancies. But, despite some regulatory approvals, this has proved to be far from straightforward in gastric cancer.Unraveling Genomic Complexity
Its molecular complexity is the most challenging feature of gastric cancer, presenting a barrier to the identification of targetable genetic aberrations. While other solid malignancies are often driven by a defining oncogene and its associated signaling pathways, gastric cancer may be driven by many such essential pathways, with distinct tumor biology for different molecular and histological subtypes.
In recognition of its complexity and poor prognosis, The Cancer Genome Atlas (TCGA) chose gastric/esophageal cancer as one of more than 20 cancers that scientists would map as part of a federally funded project launched in 2010. Investigators from major academic institutions throughout the United States and several other nations, including South Korea and Australia, used six molecular platforms to analyze 295 primary gastric adenocarcinomas. Last year, Adam J. Bass, MD, of the Dana-Farber Cancer Institute, and colleagues reported their findings in Nature
The team identified four major genomic subtypes: tumors that tested positive for the Epstein-Barr virus (9%); microsatellite unstable tumors (22%); genomically stable tumors (20%); and tumors with chromosomal instability (50%). The distribution of the subtypes differed depending on the region of the stomach, as did the tumor’s molecular profile (Figure)
Notably, the genomically stable subtype was composed mostly of diffuse-type tumors, a particularly deadly type of gastric cancer that metastasizes rapidly for which there currently is no effective treatment. The study identified novel RHOA
mutations or alterations involving activating proteins in the pathway in approximately 30% of samples in this subgroup, providing a potentially novel target for this form of gastric cancer.
Researchers hope the analysis will provide a springboard for stratifying patients for treatment and discovering new agents for testing.HER2-Targeting Success